John R. Johnson

On October 6, 2006, the U.S. Food and Drug Administration granted regular approval to vorinostat (Zolinza(R); Merck & Co., Inc., Whitehouse Station, NJ), a histone deacetylase inhibitor, for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease on or following two systemic therapies. The pivotal study supporting approval was a single-arm open-label phase II trial that enrolled 74 patients with stage IB and higher CTCL who had failed two systemic therapies (one of which must have contained bexarotene). Patients received vorinostat at a dose of 400 mg orally once daily, which could be reduced for toxicity to 300 mg daily or 300 mg 5 days a week. The median age of patients was 61 years. Sixty-one patients (82%) had stage IIB or higher CTCL and 30 patients (41%) had Sézary syndrome. The median duration of protocol treatment was 118 days. The primary efficacy endpoint was objective response assessed by the Severity-Weighted Assessment Tool. The objective response rate was 30% (95% confidence interval [CI], 19.7%-41.5%), the estimated median response duration was 168 days, and the median time to tumor progression was 202 days. An additional single-center study enrolled 33 patients with similar baseline and demographic features as the pivotal trial. Thirteen of the 33 received vorinostat (400 mg/day). The response rate in these 13 patients was 31% (95% CI, 9.1%-61.4%). The most common clinical adverse events (AEs) of any grade were diarrhea (52%), fatigue (52%), nausea (41%), and anorexia (24%). Grade 3 or 4 clinical AEs included fatigue (4%) and pulmonary embolism (5%). Hematologic laboratory abnormalities included thrombocytopenia (26%) and anemia (14%). Chemistry laboratory abnormalities included increased creatinine (16%), increased serum glucose (69%), and proteinuria (51%). Most abnormalities were National Cancer Institute Common Terminology Criteria for Adverse Events grade 1 or 2. Grade 3 or greater chemistry abnormalities included hyperglycemia, hypertriglyceridemia, and hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, hyperkalemia, hypercholesterolemia, hypophosphatemia, and increased creatinine.

BACKGROUND: Lumbar arthrodesis is commonly done in elderly patients to treat degenerative spine problems. These patients may be at increased risk for complications because of their age and associated medical conditions. In this study, we examined the rates of perioperative complications associated with posterior lumbar decompression and arthrodesis in patients sixty-five years of age or older. METHODS: We reviewed the hospital records of ninety-eight patients who were sixty-five years of age or older when they had a posterior decompression and lumbar arthrodesis with instrumentation, between 1993 and 1995, to treat degenerative disease of the spine. The average age was seventy-two years (range, sixty-five to eighty-four years). RESULTS: Perioperative complications occurred in seventy-eight patients. Twenty-one patients had at least one major complication, and sixty-nine had at least one minor complication. Forty-nine patients had more than one complication. The most common major complication was wound infection (prevalence, 10%), and the most common minor complication was urinary tract infection (prevalence, 34%). The complication rate increased with older age, increased blood loss, longer operative time, and the number of levels of the arthrodesis. CONCLUSIONS: Surgeons should be vigilant about perioperative complications in elderly patients treated with multi-level lumbar decompression and arthrodesis with instrumentation. Elderly patients should be made aware that they are at increased risk for surgical complications because of their age. Attention should be paid to controlling blood loss and limiting operative time.

How and when the Americas were populated remains contentious. Using ancient and modern genome-wide data, we found that the ancestors of all present-day Native Americans, including Athabascans and Amerindians, entered the Americas as a single migration wave from Siberia no earlier than 23 thousand years ago (ka) and after no more than an 8000-year isolation period in Beringia. After their arrival to the Americas, ancestral Native Americans diversified into two basal genetic branches around 13 ka, one that is now dispersed across North and South America and the other restricted to North America. Subsequent gene flow resulted in some Native Americans sharing ancestry with present-day East Asians (including Siberians) and, more distantly, Australo-Melanesians. Putative "Paleoamerican" relict populations, including the historical Mexican Pericúes and South American Fuego-Patagonians, are not directly related to modern Australo-Melanesians as suggested by the Paleoamerican Model.

Abstract This field study examines factors contributing to employees’ openness to participate in a planned change within a national insurance company. Drawing from recent meta‐analyses indicating that both job characteristics (JCM) and social information processing (SIP) models contribute to job attitudes, a model of factors pertaining to the change is hypothesized and tested using path analytic methods. Results indicate employees receiving “quality” information about the change and having a high need for achievement viewed the change favorably. Contrary to expectations, employees’ anxiety about the change did not influence their attitude about change. These findings are discussed in light of JCM and SIP research and their implications for research on organizational change.

PURPOSE: To summarize the end points used by the United States Food and Drug Administration (FDA) to approve new cancer drug applications over the last 13 years. MATERIALS AND METHODS: The FDA granted marketing approval to 71 oncology drug applications between January 1, 1990, and November 1, 2002. The end points used as the approval basis for each application are presented, and the rationale for each end point is discussed. RESULTS: The FDA grants either regular marketing approval or accelerated marketing approval for oncology drug applications. Regular approval is based on end points that demonstrate that the drug provides a longer life, a better life, or a favorable effect on an established surrogate for a longer life or a better life. Accelerated approval (AA) is based on a surrogate end point that is less well established but that is reasonably likely to predict a longer or a better life. Tumor response was the approval basis in 26 of 57 regular approvals, supported by relief of tumor-specific symptoms in nine of these 26 regular approvals. Relief of tumor-specific symptoms provided critical support for approval in 13 of 57 regular approvals. Approval was based on tumor response in 12 of 14 AAs. CONCLUSION: End points other than survival were the approval basis for 68% (39 of 57) of oncology drug marketing applications granted regular approval and for all 14 applications granted accelerated approval from January 1, 1990, to November 1, 2002.